Recent findings document the presence of active brown adipose tissue (BAT) in humans. Cold exposure via adrenergic stimulation activates BAT, which combusts significant amounts of blood glucose and free fatty acid (FFA) to produce heat. Animal studies suggest that BAT activation improves insulin sensitivity. However, the effect of cold-induced BAT activation on insulin sensitivity and glucose kinetics in humans remains unknown. The investigators' central hypothesis is that cold-induced BAT activation increases whole body insulin sensitivity in humans via augmented plasma glucose and FFA clearance. The specific aims of this study are to define the effects of prolonged (8h) cold exposure BAT activation on: insulin sensitivity (Aim 1); lipolysis and plasma glucose and FFA kinetics (Aim 2). Moreover, the investigators plan to investigate for alternative ways, which can activate BAT including cold water ingestion, a single meal ingestion, and a single bout of moderate intensity exercise (Aim 3). For the cold exposure study, subjects will complete 3 trials: a) 8hrs of cold exposure at their individually determined shivering threshold; b) 8hrs of cold exposure at their individually determined shivering threshold plus propranolol; c) 8hrs in thermoneutral conditions (26 - 28°C). For the rest of the arms of subjects will complete two trials: cold or tepid water ingestion, a single meal ingestion or no food ingestion, and a single bout of moderate intensity exercise or no exercise.To study the above aims, the investigators will use positron emission tomography - computed tomography, hyperinsulinemic euglycemic clamp, infusion of stable isotopes, and tissue biopsies. The findings will illuminate the role of BAT on plasma substrate regulation and insulin sensitivity and may aid in the development of lifestyle recommendations and pharmacotherapy for the prevention and treatment of diabetes and insulin resistance.

For the cold exposure trial, the subjects will follow an individualized cold exposure protocol maximize the elicited non-shivering thermogenesis. Subjects will be wearing liquid conditioned garments (Polar Products Inc, Stow, OH). The temperature will initially be set at 18°C, then decreased at 1 degree celsius intervals thought the air- conditioned temperature control bath until subjects report shivering. Electromyography (EMG; Delsys, Bagnoli 8, Boston, MA) will be performed continuously to verify shivering muscle activity. Upon shivering, the temperature will be increased by 1degree Celsius intervals until shivering resides. Subjects' core temperature will be measured at 10-second intervals with the use of a telemetric pill (Core Temp Inc., Palmetto, FL).

Other: Cold exposure plus propranolol

For the cold exposure plus propanol trial, temperature will be titrated as previously described. The non-selective beta-adrenergic antagonist propranolol (0.5mg/kg and up to 40) will be given orally before the beginning of the study and again after 4-6 hours. In case participant's heart rate after propranolol administration decreases below 50 beats per min or systolic blood pressure below 90 mmHg second dose of propranolol will not be administered. Heart rate and blood pressure will be monitored continuously throughout the study. Propranolol doses up to 80 mg have been shown to significantly reduce fludeoxyglucose (FDG) uptake in brown fat in clinical patients.

Other: Thermoneutral Conditions

Subjects will be exposed to thermoneutral conditions (26 - 28°C)

Experimental: Exercise

Subjects between 18 and 35 years old will be asked to participate in two trials: a) Exercise, i.e. four times for 10 min- at 85% VO2max (maximal oxygen consumption). with 15-min breaks between each bout b) and two weeks later rest.

Other: Thermoneutral Conditions

Subjects will be exposed to thermoneutral conditions (26 - 28°C)

Other: Exercise

Subject will be asked to complete four bouts of exercise for 10 min- at 85% of their maximal oxygen consumption (VO2max) with 15-min breaks between each bout

Eligibility

Ages Eligible for Study:

18 Years to 75 Years

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

Yes

Criteria

Inclusion Criteria:

men or women

18-75 years old

BMI 20-40 kg/m2

Exclusion Criteria:

taking diabetes medications

liver/renal/endocrine/heart disease

obstructive disease of the gastrointestinal tract

impaired gag reflex or swallowing disorder

history of GI surgery or fenilization of esophagus

GI hypomotility disorder

cancer

thyroid or hormone replacement treatment

beta-blockers

anabolic or corticosteroids the last 6 mo

pregnant/lactating women

individuals that are likely to need PET/CT in the near future for medical reasons

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01791114